An analysis of healthy adult participants from a phase 1 trial showed that treatment with ACP-204 (Acadia Pharmaceuticals), a selective inverse agonist/antagonist of serotonin 2A (5-HT2A) being developed for Alzheimer disease psychosis (ADP), led to no meaningful increases in Friderica-corrected QT (ΔQTcF) intervals.1

Presented at the 2025 Alzheimer’s Association International Conference (AAIC), held July 27-31 in Toronto, Canada, the analysis comprised 57 healthy adults to test corrected QT (QTc) intervals in single ascending oral doses of ACP-204 (10 to 180 mg) vs placebo. All told, the QTcF interval did not exceed 450 ms at any time point for any participant, and no dose-response pattern was observed. In addition, the Friderica heart rate correction met adequacy criteria, as 89.5% of participants had QTcF versus RR interval slopes <|0.045|, exceeding the 50% requirement.

QT interval prolongation is a known adverse event of many psychotropic medications because of their ability to modulate neurotransmitters. These same neurotransmitters can influence cardiac ion channels, particularly the hERG potassium channel, which is key for QT interval regulation. From a regulatory standpoint, a finding of QTcF prolongation greater than 500 ms, or changes greater than 60 ms from baseline, may lead to dose restriction, additional studies, or program discontinuation.

Led by Mona Darwish, PhD, senior director of clinical pharmacology at Acadia, a ΔQTcF of at least 30 ms and less than 60 ms was observed in 1 participant in each of the 60, 130, and 180 mg cohorts. In addition, there was one participant in the 40 mg cohort who had ΔQTcF exceed 60 ms. Overall, the changes observed using concentration-effect modeling were small and benign, with no QTcF prolongation up to 180 mg.

After subtracting the placebo ΔQTcF, the upper limit of the confidence band remained below 10 ms throughout to the maximum observed concentration of around 395 ng/mL. All told, model-predicted average placebo-adjusted ΔQTcF (ΔΔQTcF) at mean Cmax levels for all dose cohorts ranged from 3.17 ms (10 mg) to 0.47 ms (180 mg). In addition, the upper limit of the 2-sided 90% CI for ΔΔQTcF at 180 mg was 6.51 ms.

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A second presentation at AAIC 2025 looked at the effect of food consumption on the pharmacokinetics of ACP-204. This single-center, randomized, open-label, crossover, phase 1 trial included 36 healthy participants who received 60 mg dose of ACP-204, with pharmacokinetic sampling occurring on days 1-6 after drug administration. Overall, the 90% CI for the geometric mean ratio of fasted to fed for AUC0‑∞ (GMR = 115.18%), AUC0-t (GMR = 115.03%), and Cmax (GMR = 101.89%) fell within the bioequivalence limits (80% to 125%).2

Overall, these results indicated that food has no effect on the extent of ACP-204 absorption, and minimal effect on the absorption rate, which was slightly delayed (~3 h) under fed (Tmax = 8.98 hours) vs fasted (Tmax = 5.98 hours) conditions. In terms of safety, there were 4 (11.1%) drug-related treatment-emergent adverse events (TEAEs), with no serious TEAEs and no AEs leading to death or discontinuation.

An investigational agent, ACP-204 works primarily as an inverse agonist at the 5-HT2A receptor, building upon the learnings of pimavanserin (Nuplazid), Acadia’s FDA-approved medication for patients with Parkinson disease psychosis. In November 2023, Acadia began a phase 2/3 program, with its initial phase 2 trial testing the efficacy and dose response of 6 weeks of 30 or 60 mg ACP-204, or placebo, in approximately 1074 patients with ADP.

The phase 2 study, which has yet to have data read out, uses change in the Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions subscales as the primary end point, while clinician-rated improvement in symptoms served as a secondary end point. Based on the results, two phase 3 studies, currently registered, will each enroll 378 patients with ADP, for 6 weeks of treatment at 1 or both doses, against the same end points. Patients who complete the study will have the option of enrolling in a long-term open-label extension, expected to conclude in 2028.3

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REFERENCES
1. Darwish M, Mason JW, Stanworth SW, et al. Analyzing the Effect of ACP-204 on the QTc Interval in Healthy Adult Participants Using Phase 1 Study Data. Presented at: AAIC 2025; July 27-31; Toronto, Canada. ABSTRACT 105893
2. Darwish M, Dirks B, Feng X, et al. Effect of Food Consumption on the Pharmacokinetics of ACP-204, a Novel 5-HT2A Receptor Selective Antagonist/Inverse Agonist. Presented at: AAIC 2025; July 27-31; Toronto, Canada. ABSTRACT 105644
3. ACP-204. Alzforum. https://www.alzforum.org/therapeutics/acp-204. Updated February 5, 2024. Accessed August 7, 2025.